Formulation of a riluzole solution with beta- cyclodextrins

ABSTRACT

The present invention provides methods for parenterally administering riluzole to subjects in need of treatment.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is continuation of U.S. Ser. No. 15/664,937, filed Jul.31, 2017, the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides methods for parenterally administeringriluzole to subjects in need of treatment.

BACKGROUND OF THE INVENTION

Riluzole, an active pharmaceutical ingredient that has a very lowsolubility in water (i.e., about 0.3 mg/mL at neutral pH), is used totreat amyotrophic lateral sclerosis (ALS). Currently, the onlyFDA-approved dosage form of riluzole is an oral tablet, which is usuallyadministered at a dose of 50 mg every 12 hours to delay the onset ofventilator-dependence or tracheostomy. An increased rate of adverseevents including dizziness, diarrhea, and anorexia prevent higher dosesof riluzole from being administered orally. Accordingly, there remains aneed in the art for alternative treatment regimens that have an improvedsafety profile.

BRIEF DESCRIPTION OF THE FIGURES

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application with color drawing(s)will be provided by the Office by request and payment of the necessaryfee.

FIG. 1 depicts the solubility of riluzole inhydroxypropyl-beta-cyclodextrin (HP-β-CD) at room temperature after 48hours. An appropriate amount of riluzole was added to aqueous solutionsthat contained 10%, 5%, 2.5%, 1%, 0.5%, 0.25%, and 0.1% HP-β-CD, allmade isotonic with NaCl, to aqueous NaCl solution (9 mg/ml NaCl, normalsaline), and to pure water. An appropriate excess amount of riluzole wasadded to each of the sample solutions as needed to obtain saturatedsolutions of riluzole for HPLC analysis of Riluzole concentration, andto perform XRPD analysis on undissolved solid riluzole.Riluzole-containing sample suspensions were stirred at 500 rpm at roomtemperature. Supernatants were assayed after 48 hours of equilibrationby HPLC for Riluzole concentration, and undissolved solid by XRPD forcrystallinity and polymorphism.

FIG. 2 depicts the solubility of riluzole in HP-β-CD at room temperatureafter 1 week. An appropriate amount of riluzole was added to aqueoussolutions that contained 10%, 5%, 2.5%, 1%, 0.5%, 0.25%, and 0.1%HP-β-CD, all made isotonic with NaCl, to aqueous NaCl solution (9 mg/mlNaCl, normal saline), and to pure water. An appropriate excess amount ofriluzole was added to each of the sample solution as needed to obtainsaturated solutions of riluzole for HPLC analysis of Riluzoleconcentration, and to perform XRPD analysis on undissolved solidriluzole. Riluzole-containing sample suspensions were stirred at 500 rpmat room temperature. Supernatants were assayed after 48 hours ofequilibration by HPLC for Riluzole concentration, and undissolved solidby XRPD for crystallinity and polymorphism.

An appropriate amount of riluzole was added to aqueous solutions thatcontained 10%, 5%, 2.5%, 1%, 0.5%, 0.25%, and 0.1% HP-β-CD, all madeisotonic with NaCl, to aqueous NaCl solution (9 mg/ml NaCl, normalsaline), and to pure water. An appropriate excess amount of riluzole wasadded to each of the sample solution as needed to obtain saturatedsolutions of riluzole for HPLC analysis of Riluzole concentration, andto perform XRPD analysis on undissolved solid riluzole.Riluzole-containing sample suspensions were stirred at 500 rpm at roomtemperature. Supernatants were assayed after 1 week of equilibration byHPLC for Riluzole concentration, and undissolved solid by XRPD forcrystallinity and polymorphism

FIG. 3A-B depicts the XRPD patterns for residual solids recovered fromriluzole solubility experiments that were conducted in HP-β-CD at roomtemperature after 48 hours. An appropriate amount of riluzole was addedto aqueous solutions that contained 10%, 5%, 2.5%, 1%, 0.5%, 0.25%, and0.1% HP-β-CD, all made isotonic with NaCl, to aqueous NaCl solution (9mg/ml NaCl, normal saline), and to pure water. An appropriate excessamount of riluzole was added to each of the sample solution as needed toobtain saturated solutions of riluzole for HPLC analysis of Riluzoleconcentration, and to perform XRPD analysis on undissolved solidriluzole. Riluzole-containing sample suspensions were stirred at 500 rpmat room temperature. Supernatants were assayed after 48 hours ofequilibration by HPLC for Riluzole concentration, and undissolved solidby XRPD for crystallinity and polymorphism FIG. 3A depicts the XRPDpatterns for residual solids recovered from riluzole solubilized in0.5%, 1%, 2.5%, 5%, and 10% HP-β-CD as well as starting material. FIG.3B depicts the XRPD patterns for residual solids recovered from riluzolesolubilized in 0.1% and 0.25% HP-β-CD as well as water, 9 mg/ml NaCl,and starting material.

FIG. 4A-B depicts the XRPD patterns for residual solids recovered fromriluzole solubility experiments that were conducted in HP-β-CD at roomtemperature after 1 week. An appropriate amount of riluzole was added toaqueous solutions that contained 10%, 5%, 2.5%, 1%, 0.5%, 0.25%, and0.1% HP-β-CD, all made isotonic with NaCl, to aqueous NaCl solution (9mg/ml NaCl, normal saline), and to pure water. An appropriate excessamount of riluzole was added to each of the sample solution as needed toobtain saturated solutions of riluzole for HPLC analysis of Riluzoleconcentration, and to perform XRPD analysis on undissolved solidriluzole. Riluzole-containing sample suspensions were stirred at 500 rpmat room temperature. Undissolved solids were assayed after 1 week ofequilibration by XRPD for crystallinity and polymorphism. FIG. 4Adepicts the XRPD patterns for residual solids recovered from riluzolesolubilized in 0.5%, 1%, 2.5%, 5%, and 10% HP-β-CD as well as startingmaterial. FIG. 4B depicts the XRPD patterns for residual solidsrecovered from riluzole solubilized in 0.1% and 0.25% HP-β-CD as well aswater, 9 mg/ml NaCl, and starting material.

FIG. 5 depicts the XRPD patterns for residual solids recovered fromriluzole solubility experiments that were conducted in 5% HP-β-CD and 1%HP-β-CD sample solutions at 5° C. and 40° C. for 48 hours. Solubilitywas also determined in solution B (9 mg/ml NaCl) and H₂O. An appropriateexcess amount of riluzole was added to each of the sample solutions asneeded to obtain saturated solutions of riluzole and perform XRPD onundissolved solid riluzole. Samples were assayed after 48 hours by XRPD.

FIG. 6 depicts the XRPD patterns for residual solids recovered fromriluzole solubility experiments that were conducted in 5% HP-β-CD and 1%HP-β-CD sample solutions at 5° C. and 40° C. for 1 week. Solubility wasalso determined in solution B (9 mg/ml NaCl) and H₂O. An appropriateexcess amount of riluzole was added to each of the sample solutions asneeded to obtain saturated solutions of riluzole and perform XRPD onundissolved solid riluzole. Samples were assayed after 1 week by XRPD.

FIG. 7A-B depicts nervous tissue accumulation in two purpose-bredMongrel dogs that received a continuous intrathecal (IT) infusion ofriluzole (0.1 mg/hour) through a single catheter implanted between theT4 and T6 vertebrae. The animals were sacrificed after 7 or 14 days ofriluzole treatment and a necropsy was immediately performed. FIG. 7Adepicts the spread of riluzole accumulation in the spinal cord (SC)after 7 days, rostral and caudal to the catheter tip. After 7 days,riluzole accumulated at levels greater than 1000 ng/g from the T4vertebrae to the T12 vertebrae (white bars). After 14 days, riluzoleaccumulated at levels greater than 1000 ng/g from the T2 vertebrae tothe L2 vertebrae (black bars). FIG. 7B depicts the total amount ofriluzole accumulation in the spinal cord after day 7 (white bar), andday 14 (black bar).

FIG. 8A-B depicts the fluids elimination profiles of riluzole from twopurpose-bred Mongrel dogs (#1199 and #1205) that received a continuousIT infusion of riluzole (0.1 mg/hour) through a single catheterimplanted between the T4 and T6 vertebrae for 3 weeks. After stoppingthe 3-week treatment, plasma and urine were collected at timedincrements and riluzole levels were measured in the samples from dogs#1199 (white circles) and #1205 (black triangles). FIG. 8A depicts theelimination profile of riluzole from plasma of both dogs. FIG. 8Bdepicts the elimination profile of riluzole from urine of both dogs.

FIG. 9A-C depicts the CNS elimination profile of riluzole from dogs(#1199 and #1205). After a 3-week washout period, dogs #1199 (whitebars) and #1205 (black bars) received an additional continuous ITinfusion of riluzole (0.1 mg/hour) for 3 weeks. After treatment stop,plasma was collected at timed increments and riluzole levels weremeasured in the samples. 96 hours after treatment stop animals weresacrificed and a necropsy was immediately performed. FIG. 9A depicts theelimination profile of riluzole from plasma of both dogs. FIG. 9Bdepicts the riluzole concentration remaining in the brain tissue of bothdogs after the 96 hours washout. FIG. 9C depicts the riluzoleconcentration remaining in the spinal cord tissue of both dogs after the96 hours washout.

FIG. 10A-C depicts six purpose-bred Mongrel dogs that received acontinuous IT infusion of riluzole (0.25 mg/hour) through a singlecatheter implanted between the T4 and T6 vertebrae for 5 days. Afterstopping the 5-day IT treatment, plasma, urine, and CSF were collectedand riluzole levels were measured in the samples. Animals were thensacrificed and a necropsy was immediately performed. In parallel, fourMongrel dogs received an oral administration of riluzole at a humanequivalent dose of 2.6 mg/kg/day, given as twice-daily dosing (1.3 mg/kgBID) for 14 consecutive days. After stopping the 14-day oral treatment,one hour after the last pill administration, plasma, urine, and CSF werecollected and riluzole levels were measured in the samples. FIG. 10Adepicts riluzole plasma levels of dogs treated orally (circles) and dogstreated by IT infusion (triangles). FIG. 10B depicts riluzole urinelevels of dogs treated orally (circles) and dogs treated by IT infusion(triangles). FIG. 10C depicts riluzole CSF levels of dogs treated orally(circles) and dogs treated by IT infusion (triangles).

FIG. 11A-B depicts six purpose-bred Mongrel dogs that received acontinuous IT infusion of riluzole (0.25 mg/hour) through a singlecatheter implanted between the T4 and T6 vertebrae for 5 days. Afterstopping the 5-day treatment, animals were sacrificed and a necropsy wasimmediately performed. In parallel four Mongrel dogs received an oraladministration of riluzole at a human equivalent dose of 2.6 mg/kg/day,given as twice-daily dosing (1.3 mg/kg BID) for 14 consecutive days. Onehour after stopping the 14-day treatment, animals were sacrificed and anecropsy was immediately performed. FIG. 11A depicts riluzoleconcentration in brain tissue from dogs treated orally (circles) anddogs treated by IT infusion (triangles). FIG. 11B depicts riluzoleconcentration in spinal cord tissue from dogs treated orally (circles)and dogs treated by IT infusion (triangles).

FIG. 12A-B shows a comparison of the fluids and tissue concentration ofriluzole after oral administration alone or in combination with ITdelivery. FIG. 12A is a graph depicting riluzole plasma concentrationsfollowing oral riluzole (1.3 mg/kg, bid, for 10 days; grey bar) andcombination treatment with oral and IT riluzole (1.7-2 mg/kg, bid+0.20mg/h, for 5 days; blue bar). FIG. 12B is a graph depicting riluzolespinal cord (SC) concentrations vs. the distance from the catheter tipfollowing oral riluzole (1.3 mg/kg, bid, for 10 days; open circle), ITriluzole (0.25 mg/h for 5 days; closed circle) and combination treatmentwith oral and IT riluzole (1.7-2 mg/kg, bid+0.20 mg/h, for 5 days;closed square).

SUMMARY OF THE INVENTION

In an aspect, the present disclosure encompasses a method for treating asubject in need thereof, the method comprising parenterallyadministering to the subject riluzole at a dose that is less than 10 mgper day.

In another aspect, the present disclosure encompasses a method fortreating a subject in need thereof, the method comprising parenterallyadministering to the subject riluzole at a dose that is about 1 mg toabout 9 mg per day.

In an aspect, the present disclosure encompasses a method for treating asubject in need thereof, the method comprising intrathecallyadministering to the subject riluzole at a dose that is less than 10 mgper day, optionally in combination with an oral dose of riluzole.

In another aspect, the present disclosure encompasses a method fortreating a subject in need thereof, the method comprising intrathecallyadministering to the subject riluzole at a dose that is about 1 mg toabout 9 mg per day, optionally in combination with an oral dose ofriluzole.

In another aspect, the present disclosure encompasses a method fortreating a subject in need thereof, the method comprising intrathecallyadministering to the subject riluzole at a dose that is about 0.4 mg toabout 4 mg per day, optionally in combination with an oral dose ofriluzole.

In each of the above aspects, the subject in need of treatment withriluzole may be a subject with motor neuron disease, spinal muscularatrophy, spinal cord injury, Parkinson's disease, Multiple Sclerosis,Alzheimer's disease, depression, Tourette Syndrome, pain, spasticity,general anxiety disorders, schizophrenia, or bipolar disorder.

Other aspects and iterations of the invention are described morethoroughly below.

DETAILED DESCRIPTION

The present disclosure provides pharmaceutical compositions comprisingriluzole dissolved in a ß-cyclodextrin solution. In certain embodiments,these compositions also do not contain toxic excipients, or amounts ofexcipients that would be toxic when the composition is injected orinfused into a subject's brain, spinal cord, or a cerebral ventricle.Also provided herein are methods of parenterally administering apharmaceutical composition comprising riluzole dissolved in aß-cyclodextrin solution to a subject in need thereof.

(I) Pharmaceutical Compositions

One aspect of the present disclosure provides a pharmaceuticalcomposition comprising riluzole dissolved in a ß-cyclodextrin solution.Preferably, the pharmaceutical composition is iso-osmolar and has aphysiological, or close to physiological pH. Detailed below are thecomponents of the compositions and stability properties of thecompositions.

(a) Riluzole

Riluzole (2-Amino-6-(trifluoromethoxy)benzothiazole) is a sodiumchannel-blocking benzothiazole anticonvulsant drug with the followingchemical structure:

Compositions disclosed herein may contain about 0.01 mg/ml to about 45mg/ml or riluzole. In some embodiments, compositions may comprise atleast about 15 mg/ml of riluzole. For example, a composition maycomprise about 15 mg/ml, about 16 mg/ml, about 17 mg/ml, about 18 mg/ml,about 19 mg/ml, about 20 mg/ml, about 21 mg/ml, about 22 mg/ml, about 23mg/ml, about 24 mg/ml, about 25 mg/ml, about 26 mg/ml, about 27 mg/ml,about 28 mg/ml, about 29 mg/ml, about 30 mg/ml, about 31 mg/ml, about 32mg/ml, about 33 mg/ml, about 34 mg/ml, about 35 mg/ml, about 36 mg/ml,about 37 mg/ml, about 38 mg/ml, about 39 mg/ml, about 40 mg/ml, about 41mg/ml, about 42 mg/ml, about 43 mg/ml, about 44 mg/ml, or about 45 mg/mlof riluzole. In some embodiments, compositions may comprise less thanabout 15 mg/ml of riluzole. For example, a composition may compriseabout 14 mg/ml, about 13 mg/ml, about 12 mg/ml, about 11 mg/ml, about 10mg/ml, about 9 mg/ml, about 8 mg/ml, about 7 mg/ml, about 6 mg/ml, about5 mg/ml, about 4 mg/ml, about 3 mg/ml, about 2 mg/ml, about 1 mg/ml, orless of riluzole. In certain embodiments, compositions may compriseabout 0.1 mg/ml to about 10 mg of riluzole. In certain embodiments,compositions may comprise about 0.4 mg/ml to about 10 mg of riluzole. Incertain embodiments, compositions may comprise about 0.1 mg/ml to about1 mg of riluzole. In certain embodiments, compositions may compriseabout 0.4 mg/ml to about 4 mg of riluzole. In certain embodiments,compositions may comprise about 1 mg/ml to about 10 mg of riluzole. Incertain embodiments, compositions may comprise about 1 mg/ml to about 5mg of riluzole.

(b) ß-Cyclodextrin Solution

As used herein, the term “ß-cyclodextrin solution” refers to a solutioncomprising at least one ß-cyclodextrin derivative, wherein the totalamount of ß-cyclodextrin derivative in solution is at least about 1%(w/v). For example, the total amount of ß-cyclodextrin derivative insolution may be about 1% (w/v), about 2% (w/v), about 3% (w/v), about 4%(w/v), about 5% (w/v), about 6% (w/v), about 7% (w/v), about 8% (w/v),about 9% (w/v), about 10% (w/v), about 11% (w/v), about 12% (w/v), about13% (w/v), about 14% (w/v), about 15% (w/v), or more. These values canalso be used to define a range, such as from about 1% (w/v) to about 15%(w/v), about 1% (w/v) to about 10% (w/v), about 1% (w/v) to about 5%(w/v), about 5% (w/v) to about 10% (w/v), or the like. A ß-cyclodextrinsolution of the present disclosure may comprise one, two, three, four,five, or more different ß-cyclodextrin derivatives dissolved in anaqueous solvent.

(i) ß-Cyclodextrin

As used herein, the term “ß-cyclodextrin” (ß-CD) refers to a cyclicoligosaccharide having the following structure:

wherein n=1, and R is independently selected from a hydrogen, ahydrocarbon or a substituted hydrocarbyl. The term “parentß-cyclodextrin” refers to a cyclic oligosaccharide of the abovestructure, wherein R is hydrogen. The term “ß-cyclodextrin derivative”refers to a cyclic oligosaccharide of the above structure, wherein atleast one R is a hydrocarbon or a substituted hydrocarbyl.ß-cyclodextrin derivatives have increased aqueous solubility compared toparent ß-cyclodextrin.

In some embodiments, a ß-cyclodextrin derivative is selected from thegroup consisting of a sulfobutylether β-CD (SBE-β-CD), ahydroxyethyl-β-CD (HE-β-CD), a hydroxypropyl β-CD (HP-β-CD), amethyl-β-CD (M-β-CD), a dimethyl-β-CD (DM-β-CD), an ethyl-β-CD (E-β-CD),a diethyl-β-CD (DE-β-CD), a carboxymethyl-β-CD (CM-β-CD), acarboxymethyl ethyl-β-CD (CME-β-CD), a tri-O-methyl-β-CD (TRIMEB), atri-O-ethyl-β-CD (TE-β-CD), tri-O-butyryl-β-CD (TB-β-CD), atri-O-valeryl-β-CD (TV-β-CD), a di-O-hexanoyl-β-CD (DH-β-CD), aglucosyl-β-CD (G₁-β-CD), a maltosyl-β-CD (G₂-β-CD), a2-hydroxy-3-trimethyl-ammoniopropyl-β-CD (HTMAP-β-CD). In otherembodiments, a ß-cyclodextrin derivative is selected from the groupconsisting of a sulfobutylether β-CD (SBE-β-CD), a hydroxypropyl β-CD(HP-β-CD), a methyl-β-CD (M-β-CD), a dimethyl-β-CD (DM-β-CD), acarboxymethyl-β-CD (CM-β-CD), a carboxymethyl ethyl-β-CD (CME-β-CD), a2-hydroxy-3-trimethyl-ammoniopropyl-β-CD (HTMAP-β-CD). It will beappreciated that the degree and pattern of substitution for any β-CDderivative can vary. Further, for any ß-cyclodextrin derivative,substitution of the primary hydroxyl group may occur randomly, and incertain instances resulting in a mixture, or may be site-specific andresulting in a homogenous composition. Nonetheless, a skilled artisanwill be able to experimentally determine the influence, if any, thesevariations have on solubilizing riluzole based on the disclosuresherein. In an exemplary embodiment, a ß-cyclodextrin derivative isselected from the group consisting of Trappsol®2,6-di-O-methyl-β-cyclodextrin (CTD Holdings), Trappsol® HPBCD-EC(hydroxypropyl β-CD—endotoxin controlled) (CTD Holdings), Trappsol®Cyclo™ (CTD Holdings), randomly methylated Trappsol® (CTD Holdings),Captisol® (Ligand), and Beta Cyclodextrin Sulfobutyl Ethers-EthylEthers, DS 4.5, 4.5 (Ligand).

Methods for making ß-cyclodextrins are well known in the art. Forexample, parent ß-cyclodextrin can be obtained by hydrolysis of starchusing a cyclodextrin glycosyl transferase. Further details may be foundthroughout the prior art, including, but not limited to, U.S. Pat. Nos.3,812,011 and 5,118,354. Methyl-ß-cyclodextrins andethyl-ß-cyclodextrins are generally formed by alkylation of the hydroxylgroups of parent ß-cyclodextrin, while hydroxypropyl-ß-cyclodextrins andhydroxyethyl-ß-cyclodextrins are generally form by hydroxyalkylation ofthe hydroxyl groups of parent ß-cyclodextrin. Glucosyl-ß-cyclodextrinsand maltosyl-ß-cyclodextrins may be formed by substituting the primaryhydroxyl groups of parent ß-cyclodextrin with saccharides.Hydroxypropyl-ß-cyclodextrins and hydroxyethyl-ß-cyclodextrins, andtheir preparation by propylene oxide and ethylene oxide addition toparent ß-cyclodextrin, respectively, are described in a U.S. Pat. No.3,459,731, which is incorporated herein by reference. For acomprehensive review of cyclodextrins, see “Cyclodextrins and theirindustrial uses,” editor Dominique Duchene, Editions Sante, Paris, 1987.For a more recent overview, see J. Szejtli: Cyclodextrins in drugformulations; Part 1, Pharm. Techn. Int. 3(2), 15-22 (1991); and J.Szejtli: Cyclodextrins in drug formulations: Part II, Pharm. Techn. Int.3(3), 16-24 (1991).

(ii) Aqueous Solvent

Suitable aqueous solvents include any pharmaceutically acceptableaqueous solvent. In some embodiments, an aqueous solvent is sterilewater for injection. In other embodiments, an aqueous solvent is asaline solution. Suitable saline solutions may be about 0.1% (w/v) toabout 1% (w/v) sodium chloride. For example, a saline solution may beabout 0.1% (w/v), about 0.2% (w/v), about 0.3% (w/v), about 0.4% (w/v),about 0.5% (w/v), about 0.6% (w/v), about 0.7% (w/v), about 0.8% (w/v),about 0.9% (w/v), about 1% (w/v) sodium chloride. These values can alsobe used to define a range, such as from about 0.1% (w/v) to about 0.5%(w/v) sodium chloride, about 0.25% (w/v) to about 0.75% (w/v) sodiumchloride, or about 0.5% (w/v) to about 1% (w/v) sodium chloride. In yetother embodiments, an aqueous solvent is a dextrose solution. Suitabledextrose solutions may be about 2.5% (w/v) to about 5% (w/v) dextrose.For example, a saline solution may be about 2.5% (w/v), about 3% (w/v),about 3.5% (w/v), about 4% (w/v), about 4.5% (w/v), or about 5% (w/v).These values can also be used to define a range. In yet otherembodiments, an aqueous solvent is Ringer's Injection, Lactated Ringer'sInjection, or glycerol.

(iii) Concentration of ß-Cyclodextrin Derivative in Solution

The amount of ß-cyclodextrin derivative in solution may vary. In someembodiments, a solution of ß-cyclodextrin comprises at least about 1%(w/v) of ß-cyclodextrin derivative, preferably at least about 2% (w/v)of ß-cyclodextrin derivative, more preferably at least about 4% (w/v) ofß-cyclodextrin derivative. For example, a solution of ß-cyclodextrin maycomprise about 1% (w/v), about 1.5% (w/v), about 2% (w/v), about 2.5%(w/v), about 3% (w/v), about 3.5% (w/v), about 4% (w/v) ofß-cyclodextrin derivative, or more. As another example, a solution ofß-cyclodextrin may comprise about 5% (w/v), about 6% (w/v), about 7%(w/v), about 8% (w/v), about 9% (w/v), about 10% (w/v) of ß-cyclodextrinderivative, or more. As another example, a solution of ß-cyclodextrinmay comprise about 15% (w/v), about 20% (w/v), about 25% (w/v), about30% (w/v), about 35% (w/v), about 40% (w/v), about 45% (w/v) ofß-cyclodextrin derivative, or more. These values can also be used todefine a range, such as from about 1% (w/v) to about 4% (w/v), about 2%(w/v) to about 4% (w/v), or about 3% (w/v) to about 4% (w/v)ß-cyclodextrin derivative. Methods for making aqueous, ß-cyclodextrinsolutions are well known in the art, and are further detailed in theexamples.

(c) Additional Components

In some embodiments, compositions of the invention may further compriseone or more pharmaceutically acceptable excipients suitable forparenteral administration and/or one or more additional activeingredients. Non-limiting examples of excipients include preservatives(e.g. antimicrobials, antioxidants, etc.), pH modifiers and buffers,chelating agents, antimicrobial agents, tonicity-adjusting agents, andcombinations of any of these agents. The choice of suitable excipientswill be influenced, in part, by the intended route of administration.Compositions formulated to be administered as a bolus in the intrathecalspace typically will contain fewer, if any, preservatives, pH modifiersand buffers, chelating agents, antimicrobial agents, ortonicity-adjusting agents.

Non-limiting examples of preservatives include, but are not limited to,ascorbic acid and its salts, ascorbyl palmitate, ascorbyl stearate,anoxomer, N-acetylcysteine, benzyl isothiocyanate, m-aminobenzoic acid,o-aminobenzoic acid, p-aminobenzoic acid (PABA), butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid,canthaxantin, alpha-carotene, beta-carotene, beta-carotene,beta-apo-carotenoic acid, carnosol, carvacrol, catechins, cetyl gallate,chlorogenic acid, citric acid and its salts, clove extract, coffee beanextract, p-coumaric acid, 3,4-dihydroxybenzoic acid,N,N′-diphenyl-p-phenylenediamine (DPPD), dilauryl thiodipropionate,distearyl thiodipropionate, 2,6-di-tert-butylphenol, dodecyl gallate,edetic acid, ellagic acid, erythorbic acid, sodium erythorbate,esculetin, esculin, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline, ethylgallate, ethyl maltol, ethylenediaminetetraacetic acid (EDTA),eucalyptus extract, eugenol, ferulic acid, flavonoids (e.g., catechin,epicatechin, epicatechin gallate, epigallocatechin (EGC),epigallocatechin gallate (EGCG), polyphenol epigallocatechin-3-gallate),flavones (e.g., apigenin, chrysin, luteolin), flavonols (e.g.,datiscetin, myricetin, daemfero), flavanones, fraxetin, fumaric acid,gallic acid, gentian extract, gluconic acid, glycine, gum guaiacum,hesperetin, alpha-hydroxybenzyl phosphinic acid, hydroxycinammic acid,hydroxyglutaric acid, hydroquinone, N-hydroxysuccinic acid,hydroxytryrosol, hydroxyurea, rice bran extract, lactic acid and itssalts, lecithin, lecithin citrate; R-alpha-lipoic acid, lutein,lycopene, malic acid, maltol, 5-methoxy tryptamine, methyl gallate,monoglyceride citrate; monoisopropyl citrate; morin,beta-naphthoflavone, nordihydroguaiaretic acid (NDGA), octyl gallate,oxalic acid, palmityl citrate, phenothiazine, phosphatidylcholine,phosphoric acid, phosphates, phytic acid, phytylubichromel, pimentoextract, propyl gallate, polyphosphates, quercetin, trans-resveratrol,rosemary extract, rosmarinic acid, sage extract, sesamol, silymarin,sinapic acid, succinic acid, stearyl citrate, syringic acid, tartaricacid, thymol, tocopherols (i.e., alpha-, beta-, gamma- anddelta-tocopherol), tocotrienols (i.e., alpha-, beta-, gamma- anddelta-tocotrienols), tyrosol, vanilic acid,2,6-di-tert-butyl-4-hydroxymethylphenol (i.e., Ionox 100),2,4-(tris-3′,5′-bi-tert-butyl-4′-hydroxybenzyl)-mesitylene (i.e., Ionox330), 2,4,5-trihydroxybutyrophenone, ubiquinone, tertiary butylhydroquinone (TBHQ), thiodipropionic acid, trihydroxy butyrophenone,tryptamine, tyramine, uric acid, vitamin K and derivates, vitamin Q10,wheat germ oil, zeaxanthin, or combinations thereof. In an exemplaryembodiment, the preservatives are an antioxidant, such as a-tocopherolor ascorbate, and antimicrobials, such as parabens, chlorobutanol orphenol.

Non-limiting examples of pH modifiers and buffers may include citricacid, acetic acid, tartaric acid, malic acid, fumaric acid, hydrochloricacid, lactic acid, phosphoric acid, sorbic acid, succinic acid, benzoicacid, sodium acetate, sodium borate, sodium carbonate, sodiumbicarbonate, sodium phosphate, potassium phosphate, sodium hydroxide,maleic acid, sodium citrate, and sodium tartrate.

A chelating agent may be included as an excipient to immobilizeoxidative groups, including but not limited to metal ions, in order toinhibit the oxidative degradation of the riluzole by these oxidativegroups. Non-limiting examples of chelating agents include lysine,methionine, glycine, gluconate, polysaccharides, glutamate, aspartate,disodium ethylenediaminetetraacetate (Na₂EDTA), calcium disodiumethylenediaminetetraacetate, and (tri)sodium citrate.

An antimicrobial agent may be included as an excipient to minimize thedegradation of the compound according to this disclosure by microbialagents, including but not limited to bacteria and fungi. Non-limitingexamples of antimicrobials include parabens, chlorobutanol, phenol,calcium propionate, sodium nitrate, sodium nitrite, sorbic acid,Na₂EDTA, and sulfites including but not limited to sulfur dioxide,sodium bisulfite, and potassium hydrogen sulfite.

Non-limiting examples of tonicity agents include, but are not limitedto, mannitol, dextrose, sodium chloride, sorbitol, sucrose, lactose, andglycerol

(d) pH

The pH of a pharmaceutical composition of the present disclosure will beinfluenced, in part, by the intended route of administration.Compositions formulated to be administered as a bolus in the intrathecalspace may have a pH between about 3 to about 8. Compositions formulatedto be administered intravenously may have a pH between about 3 to about10.5. In some embodiments, the pH is about 3, about 3.5, about 4, about4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5 about 8,about 8.5, of about 9. In other embodiments, the pH is between about 4and about 8, or between about 5 and about 8, or between about 6 andabout 8. In still other embodiments, the pH is between about 4.5 andabout 8, or between about 4.5 and about 7.5. In yet other embodiments,the pH is between about 5 and about 7.5, or between about 5.5 and about8. In alternative embodiments, the pH is between about 5.5 and about7.5. The pH of a pharmaceutical composition may be adjusted with acidsor bases such as hydrochloric acid or sodium hydroxide, or by theaddition of a pH modifier, as described above.

(e) Osmolarity

Compositions of the present invention have an osmolarity suitable forparenteral administration. For example, compositions of the presentinvention can have an osmolarity of about 200 mOsmole to about 400mOsmole. In certain embodiments, osmolarity may be about 200 mOsmole toabout 370 mOsmole, more preferably about 240 mOsmole to about 330mOsmole, even more preferably about 260 mOsmole to about 310 mOsmole.

(f) Stability of the Compositions

Pharmaceutical compositions of the present disclosure are sufficientlystable. As used herein, the phrase “stable” refers to riluzole contentin a solution over a specified period of time and at a giventemperature, with no more than about 15% loss as compared to time zero.When the riluzole content is maintained over the specified period oftime (i.e. the loss is not more than 15%, or preferably 10%), thesolution is a “stable” riluzole formulation or riluzole solution. Anysuitable method for measuring the concentration of riluzole in solutionmay be used.

In some embodiments, the solution is stable for at least 1 week, atleast 2 weeks, at least 3 weeks, or at least 4 weeks when stored atabout 2° C. to about 8° C. In other embodiments, the solution is stablefor at least 1 month, at least 2 months, at least 3 months, or at least4 months when stored at about 2° C. to about 8° C. In other embodiments,the solution is stable for at least 5 months, at least 6 months, atleast 7 months, or at least 8 months when stored at about 2° C. to about8° C. In other embodiments, the solution is stable for at least 9months, at least 10 months, at least 11 months, or at least 12 monthswhen stored at about 2° C. to about 8° C.

In some embodiments, the solution is stable for at least 1 week, atleast 2 weeks, at least 3 weeks, or at least 4 weeks when stored at roomtemperature. In other embodiments, the solution is stable for at least 1month, at least 2 months, at least 3 months, or at least 4 months whenstored at room temperature. In other embodiments, the solution is stablefor at least 5 months, at least 6 months, at least 7 months, or at least8 months when stored at room temperature. In other embodiments, thesolution is stable for at least 9 months, at least 10 months, at least11 months, or at least 12 months when stored at room temperature.

In some embodiments, the solution is stable for at least 1 week, atleast 2 weeks, at least 3 weeks, or at least 4 weeks when stored atabout 37° C. In other embodiments, the solution is stable for at least 1month, at least 2 months, at least 3 months, or at least 4 months whenstored at about 37° C. In other embodiments, the solution is stable forat least 5 months, at least 6 months, at least 7 months, or at least 8months when stored at about 37° C. In other embodiments, the solution isstable for at least 9 months, at least 10 months, at least 11 months, orat least 12 months when stored at about 37° C.

In some embodiments, the solution is stable for at least 1 week, atleast 2 weeks, at least 3 weeks, or at least 4 weeks when stored atabout 40° C. In other embodiments, the solution is stable for at least 1month, at least 2 months, at least 3 months, or at least 4 months whenstored at about 40° C. In other embodiments, the solution is stable forat least 5 months, at least 6 months, at least 7 months, or at least 8months when stored at about 40° C. In other embodiments, the solution isstable for at least 9 months, at least 10 months, at least 11 months, orat least 12 months when stored at about 40° C.

(g) Formulation of the Compositions for Administration

Compositions provided herein are preferably formulated for parenteraladministration. The term “parenteral,” as used herein, includessubcutaneous, intravenous, intra-arterial, intramuscular, intrathecal,intra-articular, or intrasternal injection, or infusion techniques.Compositions provided herein may be packaged as single dose units (e.g.ampoules, pre-filled disposable syringes, vials,) or multiple dose unitsin volumes suitable for the route of administration. Alternatively,compositions provided herein may be packaged as an infusion solution, ora lyophilized powder for reconstitution. Formulation of pharmaceuticalcompositions is discussed in, for example, Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (1975), andLiberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y. (1980). In an exemplary embodiment,compositions provided herein are formulated for intrathecaladministration.

Briefly, compositions provided herein can be formulated by dissolvingß-cyclodextrin in an aqueous solvent; adding an amount of riluzole toobtain a desired concentration of riluzole and mixing until the riluzoleis dissolved; and adjusting the pH as needed. Each of the above stepsmay occur at room temperature, or at a temperature with a range of about±20° F. of room temperature. The final composition may be filtersterilized, or sterilized by other methods known in the art.

(h) Preferred Embodiments

In certain embodiments, a pharmaceutical composition of the presentdisclosure (a) comprises about 0.1 mg per ml to less than 10 mg per mlof riluzole dissolved in a solution comprising at least 1% (w/v)ß-cyclodextrin and an aqueous solvent; (b) has a pH of about 2.5 toabout 8, more preferably a pH of about 5 to about 8, even morepreferably a pH of about 7 to about 8; (c) has an osmolarity of about200 mOsmole to about 400 mOsmole; and (d) is optionally formulated forintrathecal administration. The pharmaceutical composition may furthercomprise one or more additional active ingredients and/or one or morepharmaceutically acceptable excipients. In preferred embodiments, theß-cyclodextrin is selected from the group consisting of2,6-di-O-methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, andsulfobutylether β-cyclodextrin, and the aqueous solvent is sterile waterfor injection or sterile saline for injection. In exemplary embodiments,the ß-cyclodextrin is selected from the group consisting of Trappsol®2,6-di-O-methyl-β-cyclodextrin (CTD Holdings), Trappsol® HPBCD-EC (CTDHoldings), Trappsol® Cyclo™ (CTD Holdings), Captisol® (Ligand), and BetaCyclodextrin Sulfobutyl Ethers-Ethyl Ethers, DS 4.5, 4.5 (Ligand).

In certain embodiments, a pharmaceutical composition of the presentdisclosure (a) consists of about 0.1 mg per ml to about 10 mg per ml ofriluzole, and optionally one or more pharmaceutically acceptableexcipients, dissolved in a solution of at least 1% (w/v) ß-cyclodextrinand an aqueous solvent; (b) has a pH of about 2.5 to about 8, morepreferably a pH of about 5 to about 8, even more preferably a pH ofabout 7 to about 8; (c) has an osmolarity of about 200 mOsmole to about400 mOsmole; and (d) is optionally formulated for intrathecaladministration. The pharmaceutical composition may further comprise oneor more additional active ingredients. In preferred embodiments, theß-cyclodextrin is selected from the group consisting of2,6-di-O-methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, andsulfobutylether β-cyclodextrin, and the aqueous solvent is sterile waterfor injection or sterile saline for injection. In exemplary embodiments,the ß-cyclodextrin is selected from the group consisting of Trappsol®2,6-di-O-methyl-β-cyclodextrin (CTD Holdings), Trappsol® HPBCD-EC (CTDHoldings), Trappsol® Cyclo™ (CTD Holdings), Captisol® (Ligand), and BetaCyclodextrin Sulfobutyl Ethers-Ethyl Ethers, DS 4.5, 4.5 (Ligand).

In certain embodiments, a pharmaceutical composition of the presentdisclosure (a) comprises about 0.4 mg per ml to about 4 mg per ml ofriluzole dissolved in a solution comprising at least 1% (w/v)ß-cyclodextrin and an aqueous solvent; (b) has a pH of about 2.5 toabout 8, more preferably a pH of about 5 to about 8, even morepreferably a pH of about 7 to about 8; (c) has an osmolarity of about200 mOsmole to about 400 mOsmole; and (d) is optionally formulated forintrathecal administration. The pharmaceutical composition may furthercomprise one or more additional active ingredients and/or one or morepharmaceutically acceptable excipients. In preferred embodiments, theß-cyclodextrin is selected from the group consisting of2,6-di-O-methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, andsulfobutylether β-cyclodextrin, and the aqueous solvent is sterile waterfor injection or sterile saline for injection. In exemplary embodiments,the ß-cyclodextrin is selected from the group consisting of Trappsol®2,6-di-O-methyl-β-cyclodextrin (CTD Holdings), Trappsol® HPBCD-EC (CTDHoldings), Trappsol® Cyclo™ (CTD Holdings), Captisol® (Ligand), and BetaCyclodextrin Sulfobutyl Ethers-Ethyl Ethers, DS 4.5, 4.5 (Ligand).

In certain embodiments, a pharmaceutical composition of the presentdisclosure (a) consists of about 0.4 mg per ml to about 4 mg per ml ofriluzole, and optionally one or more pharmaceutically acceptableexcipients, dissolved in a solution of at least 1% (w/v) ß-cyclodextrinand an aqueous solvent; (b) has a pH of about 2.5 to about 8, morepreferably a pH of about 5 to about 8, even more preferably a pH ofabout 7 to about 8; (c) has an osmolarity of about 200 mOsmole to about400 mOsmole; and (d) is optionally formulated for intrathecaladministration. The pharmaceutical composition may further comprise oneor more additional active ingredients. In preferred embodiments, theß-cyclodextrin is selected from the group consisting of2,6-di-O-methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, andsulfobutylether β-cyclodextrin, and the aqueous solvent is sterile waterfor injection or sterile saline for injection. In exemplary embodiments,the ß-cyclodextrin is selected from the group consisting of Trappsol®2,6-di-O-methyl-β-cyclodextrin (CTD Holdings), Trappsol® HPBCD-EC (CTDHoldings), Trappsol® Cyclo™ (CTD Holdings), Captisol® (Ligand), and BetaCyclodextrin Sulfobutyl Ethers-Ethyl Ethers, DS 4.5, 4.5 (Ligand).

In certain embodiments, a pharmaceutical composition of the presentdisclosure (a) comprises about 0.1 mg per ml to about 10 mg per ml ofriluzole dissolved in a solution comprising about 1% to about 10% (w/v)ß-cyclodextrin and an aqueous solvent; (b) has a pH of about 2.5 toabout 8, more preferably a pH of about 5 to about 8, even morepreferably a pH of about 7 to about 8; (c) has an osmolarity of about200 mOsmole to about 400 mOsmole; and (d) is optionally formulated forintrathecal administration. The pharmaceutical composition may furthercomprise one or more additional active ingredients and/or one or morepharmaceutically acceptable excipients. In preferred embodiments, theß-cyclodextrin is selected from the group consisting of2,6-di-O-methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, andsulfobutylether β-cyclodextrin, and the aqueous solvent is sterile waterfor injection or sterile saline for injection. In exemplary embodiments,the ß-cyclodextrin is selected from the group consisting of Trappsol®2,6-di-O-methyl-β-cyclodextrin (CTD Holdings), Trappsol® HPBCD-EC (CTDHoldings), Trappsol® Cyclo™ (CTD Holdings), Captisol® (Ligand), and BetaCyclodextrin Sulfobutyl Ethers-Ethyl Ethers, DS 4.5, 4.5 (Ligand).

In certain embodiments, a pharmaceutical composition of the presentdisclosure (a) consists of 0.1 mg per ml to about 10 mg per ml ofriluzole, and optionally one or more pharmaceutically acceptableexcipients, dissolved in a solution of about 1% to about 15% (w/v)ß-cyclodextrin and an aqueous solvent; (b) has a pH of about 2.5 toabout 8, more preferably a pH of about 5 to about 8, even morepreferably a pH of about 7 to about 8; (c) has an osmolarity of about200 mOsmole to about 400 mOsmole; and (d) is optionally formulated forintrathecal administration. The pharmaceutical composition may furthercomprise one or more additional active ingredients. In preferredembodiments, the ß-cyclodextrin is selected from the group consisting of2,6-di-O-methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, andsulfobutylether β-cyclodextrin, and the aqueous solvent is sterile waterfor injection or sterile saline for injection. In exemplary embodiments,the ß-cyclodextrin is selected from the group consisting of Trappsol®2,6-di-O-methyl-β-cyclodextrin (CTD Holdings), Trappsol® HPBCD-EC (CTDHoldings), Trappsol® Cyclo™ (CTD Holdings), Captisol® (Ligand), and BetaCyclodextrin Sulfobutyl Ethers-Ethyl Ethers, DS 4.5, 4.5 (Ligand).

In certain embodiments, a pharmaceutical composition of the presentdisclosure (a) comprises about 0.4 mg per ml to about 4 mg per ml ofriluzole dissolved in a solution comprising about 0.4% to about 4% (w/v)ß-cyclodextrin and an aqueous solvent; (b) has a pH of about 2.5 toabout 8, more preferably a pH of about 5 to about 8, even morepreferably a pH of about 7 to about 8; (c) has an osmolarity of about200 mOsmole to about 400 mOsmole; and (d) is optionally formulated forintrathecal administration. The pharmaceutical composition may furthercomprise one or more additional active ingredients and/or one or morepharmaceutically acceptable excipients. In preferred embodiments, theß-cyclodextrin is selected from the group consisting of2,6-di-O-methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, andsulfobutylether β-cyclodextrin, and the aqueous solvent is sterile waterfor injection or sterile saline for injection. In exemplary embodiments,the ß-cyclodextrin is selected from the group consisting of Trappsol®2,6-di-O-methyl-β-cyclodextrin (CTD Holdings), Trappsol® HPBCD-EC (CTDHoldings), Trappsol® Cyclo™ (CTD Holdings), Captisol® (Ligand), and BetaCyclodextrin Sulfobutyl Ethers-Ethyl Ethers, DS 4.5, 4.5 (Ligand).

In certain embodiments, a pharmaceutical composition of the presentdisclosure (a) consists of about 0.4 mg per ml to about 4 mg per ml ofriluzole, and optionally one or more pharmaceutically acceptableexcipients, dissolved in a solution of about 0.4% to about 4% (w/v)ß-cyclodextrin and an aqueous solvent; (b) has a pH of about 2.5 toabout 8, more preferably a pH of about 5 to about 8, even morepreferably a pH of about 7 to about 8; (c) has an osmolarity of about200 mOsmole to about 400 mOsmole; and (d) is optionally formulated forintrathecal administration. The pharmaceutical composition may furthercomprise one or more additional active ingredients. In preferredembodiments, the ß-cyclodextrin is selected from the group consisting of2,6-di-O-methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, andsulfobutylether β-cyclodextrin, and the aqueous solvent is sterile waterfor injection or sterile saline for injection. In exemplary embodiments,the ß-cyclodextrin is selected from the group consisting of Trappsol®2,6-di-O-methyl-β-cyclodextrin (CTD Holdings), Trappsol® HPBCD-EC (CTDHoldings), Trappsol® Cyclo™ (CTD Holdings), Captisol® (Ligand), and BetaCyclodextrin Sulfobutyl Ethers-Ethyl Ethers, DS 4.5, 4.5 (Ligand).

In certain embodiments, a pharmaceutical composition of the presentdisclosure (a) comprises about 1 mg per ml to about 5 mg per ml ofriluzole dissolved in a solution comprising about 1% to about 5% (w/v)ß-cyclodextrin and an aqueous solvent; (b) has a pH of about 2.5 toabout 8, more preferably a pH of about 5 to about 8, even morepreferably a pH of about 7 to about 8; (c) has an osmolarity of about200 mOsmole to about 400 mOsmole; and (d) is optionally formulated forintrathecal administration. The pharmaceutical composition may furthercomprise one or more additional active ingredients and/or one or morepharmaceutically acceptable excipients. In preferred embodiments, theß-cyclodextrin is selected from the group consisting of2,6-di-O-methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, andsulfobutylether β-cyclodextrin, and the aqueous solvent is sterile waterfor injection or sterile saline for injection. In exemplary embodiments,the ß-cyclodextrin is selected from the group consisting of Trappsol®2,6-di-O-methyl-β-cyclodextrin (CTD Holdings), Trappsol® HPBCD-EC (CTDHoldings), Trappsol® Cyclo™ (CTD Holdings), Captisol® (Ligand), and BetaCyclodextrin Sulfobutyl Ethers-Ethyl Ethers, DS 4.5, 4.5 (Ligand).

In certain embodiments, a pharmaceutical composition of the presentdisclosure (a) consists of about 1 mg per ml to about 5 mg per ml ofriluzole, and optionally one or more pharmaceutically acceptableexcipients, dissolved in a solution of about 1% to about 5% (w/v)ß-cyclodextrin and an aqueous solvent; (b) has a pH of about 2.5 toabout 8, more preferably a pH of about 5 to about 8, even morepreferably a pH of about 7 to about 8; (c) has an osmolarity of about200 mOsmole to about 400 mOsmole; and (d) is optionally formulated forintrathecal administration. The pharmaceutical composition may furthercomprise one or more additional active ingredients. In preferredembodiments, the ß-cyclodextrin is selected from the group consisting of2,6-di-O-methyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, andsulfobutylether β-cyclodextrin, and the aqueous solvent is sterile waterfor injection or sterile saline for injection. In exemplary embodiments,the ß-cyclodextrin is selected from the group consisting of Trappsol®2,6-di-O-methyl-β-cyclodextrin (CTD Holdings), Trappsol® HPBCD-EC (CTDHoldings), Trappsol® Cyclo™ (CTD Holdings), Captisol® (Ligand), and BetaCyclodextrin Sulfobutyl Ethers-Ethyl Ethers, DS 4.5, 4.5 (Ligand).

(II) Methods for Administering the Compositions

The present disclosure provides methods for treating a subject in needthereof by parenterally administering riluzole at a dose that is lessthan 10 mg per day. Bolus administration and continuous administrationare possible. Riluzole may be administered alone or in combination withone or more additional active ingredients. In preferred embodiments,riluzole is formulated as a composition of Section I.

In some embodiments, riluzole is administered into the subject's brain,spinal cord, or a cerebral ventricle. In preferred embodiments, riluzoleis intrathecally administered. In each of the above embodiments, thedaily dose may be less than 10 mg, less than 9 mg, less than 8 mg, lessthan 7 mg, less than 6 mg, or less than 5 mg. Alternatively, the dailydose may be less than 4 mg, less than 3 mg, less than 2 mg or less than1 mg.

In embodiments where riluzole is intrathecally administered oradministered into a subject's brain, spinal cord, or a cerebralventricle, continuous administration is preferred. For example, riluzolemay be administered continuously by a pump at a dose that is less than10 mg every 24 hours, more particularly for example, at a dose that isabout 0.4 mg or greater but less than 10 mg every 24 hours. In certainembodiments, the dose may be about 0.4 mg to about 4 mg every 24 hours,about 0.1 mg to about 4 mg every 24 hours, or 1 mg to about 4 mg every24 hours. In other embodiments, the dose may be about 0.1 mg to lessthan 10 mg every 24 hours, about 0.1 mg to about 9 mg every 24 hours,about 1 mg to about 9 mg every 24 hours, or about 4 mg to about 9 mgevery 24 hours. Administration can continue for, typically, at leastabout one day and may continue for about 12 months or longer asnecessary to treat the subject. Those of skill in the art willappreciate that the infusion rate (i.e. ml/day of a riluzolecomposition) needed to achieve the above dose will vary depending uponthe riluzole concentration in the pharmaceutical composition that isbeing administered.

Administration can continue for about 1 day, 2 days, 3 days, 4 days, 5days, 6 days, one week, two weeks, three weeks, one month, two months,three months, six months, nine months, twelve months, or more. In someinstances, the dose of riluzole escalates over the course of thetherapy. For example, patients may begin therapy at about 0.4 mg/day,and may be increased to about 1 mg/day, about 4 mg/day, or even higherover the course of treatment.

Alternatively, intrathecal administration of riluzole can be interruptedby one or more drug holidays. For example, treatment may be carried outby repeating an administration period and a drug holiday period. Theadministration period and the drug holiday may be of equal or varyingduration. For example, riluzole may be intrathecally administered forabout 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, twoweeks, three weeks, or four weeks followed by a drug holiday period ofabout 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, twoweeks, three weeks, or four weeks. Each repetition (or cycle) oftreatment may be the same, or the treatment period and/or drug holidayperiod may vary between cycles. The number of repetitions is notparticularly limited, as long as it is two or more.

It has also been surprisingly discovered that a combination of orallyadministered riluzole and intrathecally administered riluzole is safeand does not substantially increase peripheral exposure in comparisonwith intrathecal administration only. Peripheral exposure may bemeasured by any method known in the art including, but not limited to,the concentration of riluzole (or a metabolite) measured in a biologicalsample (e.g. serum, urine, etc.) or serum AUC for riluzole (or ametabolite). Accordingly, in each of the above embodiments, a subjectmay also be administered an oral dose of riluzole that does not exceedthe maximal, oral daily dose (e.g., 100 mg per day or 50 mg BID).

As used herein, the terms “treat,” “treating,” or “treatment” refer toboth therapeutic treatment and prophylactic or preventative measures,wherein the object is to prevent or slow down (lessen) an undesiredphysiological change or disease/disorder as compared to an untreatedsubject. Beneficial or desired clinical results include, but are notlimited to, alleviation of symptoms, diminishment of extent of disease,stabilized (i.e., not worsening) state of disease, a delay or slowing ofdisease progression, amelioration or palliation of the disease state,and remission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment.

Subjects in need of treatment include those already with the disease,condition, or disorder as well as those prone to have the disease,condition or disorder or those in which the disease, condition ordisorder is to be prevented. Preferred subjects are mammals, morepreferably humans.

In some embodiments, the present disclosure provides a method fortreating a subject with motor neuron disease (MND), preferablyamyotrophic lateral sclerosis (ALS). Examples of the symptoms caused byMND include clinical symptoms such as a decrease in respiratoryfunction, spoken language disorder, dysphagia, or limb movementdisorder. Treatment of MND may include, but is not limited to, improvinga symptom of MND, extending survival of the subject, extending time totracheostomy of the subject, slowing the rate of functional decline ofthe subject, or any combination thereof.

In some embodiments, a subject in need thereof is a subject with spinalmuscular atrophy. Treatment of spinal muscular atrophy may include, butis not limited to, extending survival of the subject, extending time totracheostomy of the subject, slowing the rate of functional decline ofthe subject, or any combination thereof.

In other embodiments, a subject in need thereof is a subject withParkinson's disease. Treatment of Parkinson's disease may include, butis not limited to, extending survival of the subject, slowing the rateof functional decline of the subject, or any combination thereof.

In other embodiments, a subject in need thereof is a subject withMultiple Sclerosis. Treatment of Multiple Sclerosis may include, but isnot limited to, neuroprotection (e.g., slowing the rate of brain volumeloss, brain volume change, demyelination, functional decline, etc., orany combination thereof).

In other embodiments, a subject in need thereof is a subject withtraumatic or non-traumatic spinal cord injury. Traumatic spinal cordinjury results from mechanical disruption of the spinal cord tissue.Non-traumatic spinal cord injury results from a variety of disordersincluding, but not limited to, spondylosis, tumors and infection.Treatment of a spinal cord injury may include, but is not limited to,improvements in overall neurologic recovery, sensory recovery,functional outcomes, quality of life outcomes, health utilities, as wella decrease in mortality, or any combination thereof.

In other embodiments, a subject in need thereof is a subject withAlzheimer's disease. Treatment of Alzheimer's disease may include, butis not limited to, improving cognitive function or slowing the rate offunctional decline (e.g., as measured by standard tests known in theart), reducing glutamate levels in the brain, improving pathologicalbiomarkers (e.g., amyloid beta plaques, levels of tau, phospho-tau, orvarious amyloid beta peptides, etc.), or any combination thereof.

In other embodiments, a subject in need thereof is a subject with painor spasticity, and treating reduces the severity, duration and/orfrequency of the pain or spasticity.

In other embodiments, a subject in need thereof is a subject with apsychiatric disorder such as depression, Tourette Syndrome, generalanxiety disorders, schizophrenia, bipolar disorder, and treatingimproves a clinical symptom diagnostic of the psychiatric disorder.

Definitions

When introducing elements of the embodiments described herein, thearticles “a”, “an”, “the” and “said” are intended to mean that there areone or more of the elements. The terms “comprising”, “including” and“having” are intended to be inclusive and mean that there may beadditional elements other than the listed elements.

The term “about,” as used herein, refers to ±10%. For example, “about”includes ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, and ±1%.

The term “acyl,” as used herein alone or as part of another group,denotes the moiety formed by removal of the hydroxyl group from thegroup COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R is R¹,R¹O—, R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstituted hydrocarbyl,or heterocyclo, and R² is hydrogen, hydrocarbyl, or substitutedhydrocarbyl.

The term “acyloxy,” as used herein alone or as part of another group,denotes an acyl group as described above bonded through an oxygenlinkage (O), e.g., RC(O)O— wherein R is as defined in connection withthe term “acyl.”

The term “allyl,” as used herein not only refers to a compoundcontaining the simple allyl group (CH₂═CH—CH₂—), but also to compoundsthat contain substituted allyl groups or allyl groups forming part of aring system.

The term “alkyl” as used herein describes groups which are preferablylower alkyl containing from one to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainor cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl andthe like.

The term “alkenyl” as used herein describes groups which are preferablylower alkenyl containing from two to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainor cyclic and include ethenyl, propenyl, isopropenyl, butenyl,isobutenyl, hexenyl, and the like.

The term “alkynyl” as used herein describes groups which are preferablylower alkynyl containing from two to eight carbon atoms in the principalchain and up to 20 carbon atoms. They may be straight or branched chainand include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and thelike.

The term “aromatic” as used herein alone or as part of another groupdenotes optionally substituted homo- or heterocyclic conjugated planarring or ring system comprising delocalized electrons. These aromaticgroups are preferably monocyclic (e.g., furan or benzene), bicyclic, ortricyclic groups containing from 5 to 14 atoms in the ring portion. Theterm “aromatic” encompasses “aryl” groups defined below.

The terms “aryl” or “Ar” as used herein alone or as part of anothergroup denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 10 carbonsin the ring portion, such as phenyl, biphenyl, naphthyl, substitutedphenyl, substituted biphenyl, or substituted naphthyl.

The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

The “substituted hydrocarbyl” moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbon,including moieties in which a carbon chain atom is substituted with aheteroatom such as nitrogen, oxygen, silicon, phosphorous, boron, or ahalogen atom, and moieties in which the carbon chain comprisesadditional substituents. These substituents include alkyl, alkoxy, acyl,acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal,carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo,hydroxy, keto, ketal, phospho, nitro, and thio.

The terms “heterocyclo” or “heterocyclic” as used herein alone or aspart of another group denote optionally substituted, fully saturated orunsaturated, monocyclic or bicyclic, aromatic or non-aromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to theremainder of the molecule through a carbon or heteroatom. Exemplaryheterocyclo groups include heteroaromatics as described above. Exemplarysubstituents include one or more of the following groups: hydrocarbyl,substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl,alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo,cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal,phospho, nitro, and thio.

The term “parenteral,” as used herein, includes subcutaneous,intravenous, intra-arterial, intramuscular, intrathecal, or intrasternalinjection, or infusion techniques.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples that follow representtechniques discovered by the inventors to function well in the practiceof the invention. Those of skill in the art should, however, in light ofthe present disclosure, appreciate that changes may be made in thespecific embodiments that are disclosed and still obtain a like orsimilar result without departing from the spirit and scope of theinvention. Therefore, all matter set forth or shown in the accompanyingdrawings is to be interpreted as illustrative and not in a limitingsense.

EXAMPLES

The following examples illustrate various iterations of the invention.

Example 1. Studies of Riluzole

Solubility. To test the solubility of riluzole inhydroxypropyl-beta-cyclodextrin (HP-β-CD), stock solutions were firstprepared where stock solution A contained 50 ml of 10% (100 mg/ml)HP-β-CD and 5.5 mg/ml NaCl in H₂O and stock solution B contained 9 mg/mlNaCl in H₂O. Stock solutions were used to prepare the following samplesolutions for testing (all isotonic with NaCl): 10%, 5%, 2.5%, 1%, 0.5%,0.25%, and 0.1% HP-β-CD. Solubility was also determined in stocksolution B (9 mg/ml NaCl) and in pure H₂O. An appropriate excess amountof riluzole was added to each of the sample solution as needed to obtaina saturated solution of riluzole for determination of concentration inthe supernatant (equilibrium solubility) by HPLC, and to perform X-Raypowder diffraction (XRPD) on the undissolved riluzole.Riluzole-containing sample solutions were stirred at 500 rpm and allowedto equilibrate at room temperature. (Saturated) solutions of Riluzolewere separated from the undissolved solid Riluzole after 48 hours andafter 1 week of equilibration. Solutions were analyzed for Riluzoleconcentration by HPLC to obtain equilibrium solubility of riluzole.Undissolved solid samples were assayed by XRPD to confirm crystallinityand to confirm crystal form did not change (i.e., no new polymorphs).

Data show that the solubility of riluzole increased linearly with theincreasing concentration of HP-β-CD after 48 hours (FIG. 1) or 1 week(FIG. 2). Further, there was no crystal form change in riluzole at anyconcentration of HP-β-CD after 48 hours (FIG. 3A and FIG. 3B) or 1 week(FIG. 4A and FIG. 4B).

Solubility of riluzole was determined in 5% HP-β-CD and 1% HP-β-CDsample solutions at 5° C. and 40° C. for 48 hours and 1 week. Stocksolution B (9 mg/ml NaCl) and H₂O were used as sample solution blanks.Solubility of riluzole at 5° C. and 40° C. was consistent with riluzolesolubility at room temperature. No form change in riluzole occurred atany concentration of HP-β-CD after 48 hours (FIG. 5) or 1 week (FIG. 6).

Next, 1 mg/ml riluzole was added to three solutions, each containing 1%HP-β-CD, 0.8% NaCl and 5 mM sodium phosphate buffer, prior to adjustingthe pH to 6.3, 7.2 and 7.9 respectively. Similarly, 5 mg/ml riluzole wasadded to three solutions, each containing 5.5% HP-β-CD, 0.65% NaCl and 5mM sodium phosphate buffer, prior to adjusting the pH to 6.3, 7.2 and7.9 respectively. All samples were placed in stability chambersmaintained at either 5° C., 50° C. or 70° C. After all samples wereincubated for 12 days at the respective temperatures, chemical stabilitywas assessed. All experimental solutions of riluzole showed goodsolution stability at 5° C., 50° C. or 70° C. after 12-day incubation(Table 1).

TABLE 1 Area Riluzole Temp. Assay of API (mg/ml) Buffer (° C.) (%) (%) 11% Trappsol ® HPBCD-EC + 5 98.9 100.00 1 0.8% NaCl + 5 mM 50 99.5 100.001 sodium phosphate buffer 70 97.6 100.00 (pH 6.3) 1 1% Trappsol ®HPBCD-EC + 5 99.5 100.00 1 0.8% NaCl + 5 mM 50 101.5 100.00 1 sodiumphosphate buffer 70 99.3 100.00 (pH 7.2) 1 1% Trappsol ® HPBCD-EC + 599.2 100.00 1 0.8% NaCl + 5 mM 50 100.5 100.00 1 sodium phosphate buffer70 98.9 100.00 (pH 7.9) 5 5.5% Trappsol ® HPBCD-EC + 5 99.0 100.00 50.65% NaCl + 5 mM 50 99.6 100.00 5 sodium phosphate buffer 70 99.0100.00 (pH 6.3) 5 5.5% Trappsol ® HPBCD-EC + 5 99.1 100.00 5 0.65%NaCl + 5 mM 50 99.7 100.00 5 sodium phosphate buffer 70 98.6 100.00 (pH7.2) 5 5.5% Trappsol ® HPBCD-EC + 5 98.9 100.00 5 0.65% NaCl + 5 mM 5099.6 100.00 5 sodium phosphate buffer 70 100.0 100.00 (pH 7.9)

Nervous Tissue Accumulation.

Two purpose-bred Mongrel dogs received a continuous intrathecal (IT)infusion of riluzole (0.1 mg/hour) through a single catheter implantedbetween the T4 and T6 vertebrae. Animals were sacrificed after 7 or 14days of riluzole treatment and a necropsy was immediately performed.After 7 days, riluzole spread rostral and caudal to the catheter tip inthe spinal cord (SC) and accumulated at levels greater than 1000 ng/gfrom the T4 vertebrae to the T12 vertebrae. After 14 days, riluzoleaccumulated at levels greater than 1000 ng/g from the T2 vertebrae tothe L2 vertebrae (FIG. 7A). Total riluzole accumulation increased overtime (FIG. 7B).

In a separate study, two purpose-bred Mongrel dogs (#1199 and #1205)received a continuous IT infusion of riluzole (0.1 mg/hour) through asingle catheter implanted between the T4 and T6 vertebrae for 3 weeks.After stopping the 3-week treatment, plasma and urine were collected attimed increments and riluzole levels were measured in the samples. Theelimination half-life of riluzole from plasma was 12 hours and 14 hoursfor dogs #1199 and #1205, respectively (FIG. 8A). Riluzole was largelyeliminated by the kidneys in urine (FIG. 8B).

Three-week treated animals did not receive treatment for the following 3weeks. After this 3-week washout period, dogs #1199 and #1205 receivedan additional continuous IT infusion of riluzole (0.1 mg/hour) for 3weeks. After stopping the 3-weeks of additional riluzole treatment,plasma, urine, and CSF were collected at timed increments and riluzolelevels were measured in the samples. 96 hours after treatment stop,animals were sacrificed and a necropsy was immediately performed. Theelimination half-life of riluzole from plasma was 18 hours and 28 hoursfor dogs #1199 and #1205, respectively (FIG. 9A). Riluzole accumulationin brain tissue (FIG. 9B) and the spinal cord (FIG. 9C) was minimal (<15ng/g) in both animals following the 96-hour washout period.

Dose Range Finding Studies.

Six purpose-bred Mongrel dogs received a continuous IT infusion ofriluzole (0.25 mg/hour) through a single catheter implanted between theT4 and T6 vertebrae for 5 days. After stopping the 5-day treatment,plasma, urine, and CSF were collected and riluzole levels were measuredin the samples. Animals were then sacrificed and a necropsy wasimmediately performed. In parallel, four Mongrel dogs received an oraladministration of riluzole at a human equivalent dose of 2.6 mg/kg/day,given as twice-daily dosing (1.3 mg/kg BID) for 14 consecutive days.After stopping the 14-day treatment, one hour after the last pilladministration, plasma, urine, and CSF were collected and riluzolelevels were measured in the samples. Animals were then sacrificed and anecropsy was immediately performed.

Riluzole levels in plasma collected from 14-day, oral-treated dogs wasapproximately 20-fold higher compared to levels in plasma from 5-day,IT-treated dogs (FIG. 10A). Riluzole levels in urine collected from14-day, oral-treated dogs was approximately 3-fold higher compared tolevels in urine from 5-day, IT-treated dogs (FIG. 10B). Riluzole levelsin CSF collected from 14-day, oral-treated dogs was similar to levels inCSF from 5-day, IT-treated dogs (FIG. 10C). Riluzole accumulation inbrain tissue was approximately 700-fold higher in 14-day, oral-treateddogs compared to brain tissue of 5-day, IT-treated dogs (FIG. 11A).However, riluzole accumulation in the spinal cord was approximately4-fold higher in 5-day, IT-treated dogs compared to spinal cord tissueharvested from 14-day, oral-treated dogs (FIG. 11B).

Example 2. Riluzole Formulation

In one embodiment, riluzole is formulated for intrathecal administrationas follows.

Composition:

Ingredient Concentration Amount for 100 ml RIluzole 4 mg/ml 400 mgTrappsol ® HPBCD-EC 40 mg/ml 4000 mg Sodium chloride, USP 7.5 mg/ml 750mg Sodium Phosphate Dibasic 0.142 mg/ml 14.2 mg Anhydrous, USP (1 mM)0.1N HCl and/or 0.1N qs. pH 7.40 qs. pH 7.40 NaOH WFI (water forinjection) qs. 1 ml qs. 100 ml

Procedure:

-   -   1. Add 25 ml of water for injection to a 200 ml beaker and        initiate stirring.    -   2. Dissolve 14.2 mg of Dibasic Sodium Phosphate.    -   3. Dissolve 750 milligrams of sodium chloride.    -   4. Adjust the pH to 7.4 with 0.1 N HCl.    -   5. Add 4000 milligrams of Trappsol® HPBCD-EC and allow it to        dissolve.    -   6. Add 400 milligrams of riluzole and allow it to dissolve.    -   7. Add 65 ml of water for injection.    -   8. Adjust pH to 7.40 if necessary with 0.01 N HCl or 0.01 N        NaOH, whichever is needed.    -   9. Quantitatively transfer the solution from beaker to        volumetric flask. Rinse the beaker twice consecutively with 4 ml        with WFI and use rinses to make the volume to exactly 100 ml.

Example 3. Riluzole Formulation

In one embodiment, riluzole is formulated for intrathecal administrationas follows.

Composition:

Ingredient Concentration Amount for 10 liters* RIluzole 4.00 mg/ml 40.0grams Trappsol ® HPBCD-EC 40.0 mg/ml 400 grams Sodium Phosphate 7.20mg/ml 72.0 grams Monobasic, Monohydrate, USP Sodium Phosphate Dibasic,0.30 mg/ml 3.00 grams Anhydrous, USP (2.2 mM) 0.1N HCl and/or 0.1N 0.40mg/ml 4.00 grams NaOH (2.8 mM) WFI (water for injection) qs. pH 7.30 qs.pH 7.30 *Formulation density = 1.016 g/ml

Procedure:

-   -   1. Tare a 4 L beaker and charge it with 2.0 kg of WFI.    -   2. Initiate gentle stirring with magnetic stir bar.    -   3. Add:        -   3.00 grams of Sodium Phosphate Monobasic, Monohydrate        -   4.00 grams of Sodium Phosphate Dibasic, Anhydrous        -   72.0 grams of NaCl        -   400 grams of Trappsol® HPBCD-EC    -   4. Allow all solid components to dissolve. Increase stirring        speed if needed.    -   5. Add 40.0 grams of riluzole and allow it to dissolve. (This        may take several hours.)    -   6. Tare a 5 gallon Nalgene tank and charge it with 3.0 kg of        WFI.    -   7. Pour the contents of the 4 L Beaker from step 5 (except the        stir bar) into the tank.    -   8. Rinse the inside of the 4 L beaker a minimum of 3 times with        1 liter of WFI, each time pouring the rinsing into the Nalgene        tank.    -   9. Q.S. the solution using WFI to 9.50+/−0.02 kg.    -   10. Initiate mixing with mechanical stirrer.    -   11. While mixing, adjust the pH of the solution to 7.30. Use the        1N HCl to adjust the pH down or the 1N NaOH to adjust the pH up.    -   12. Mix the solution for a minimum of 15 minutes or until the        solution is uniform, whichever is longer.    -   13. Q.S. the solution to 10.16 kg with WFI.    -   14. Check the pH. If pH is outside 7.25-7.35 range use the 1N        HCl to adjust the pH down, or the 1N NaOH to adjust the pH up.    -   15. Sterile filter into an appropriate sterile receiving vessel.    -   16. Under aseptic conditions, fill the formulation into sterile        vials, stopper and cap vials.

Example 4. Riluzole Formulation

In one embodiment, riluzole is formulated for intrathecal administrationas follows:

Composition:

Ingredient Quantity RIluzole 4 mg/ml Trappsol ®EC 40 mg/ml SodiumPhosphate Dibasic 0.71 mg/ml Anhydrous, USP Sodium chloride, USP 7.20mg/ml 0.1N HCl qs. pH 7.30 WFI (water for injection) qs. 1 mlProcedure for 10-liter batch compounding:

-   -   1. Tare a 4 L beaker and charge it with 2.0 kg of WFI.    -   2. Initiate gentle stirring with magnetic stir bar.    -   3. Add 7.10 grams of Sodium Phosphate Dibasic, Anhydrous    -   4. Add 72.0 grams of NaCl    -   5. Adjust pH to 6-9 (preferably 7.5-8.5). Use 1N HCl to adjust        the pH down, or 1N NaOH to adjust the pH up.    -   6. Add 400 grams of Trappsol® EC    -   7. Add 40.0 grams of riluzole.    -   8. Allow all solid components to dissolve. Increase stirring        speed if needed. (This may take several hours.)    -   9. Tare a 5 gallon Nalgene tank and charge it with 3.0 kg of        WFI.    -   10. Pour the contents of the 4 L Beaker from step 8 (except the        stir bar) into the tank.    -   11. Rinse the inside of the 4 L beaker a minimum of 3 times with        1 liter of WFI, each time pouring the rinsing into the Nalgene        tank.    -   12. Q.S. the solution using WFI to 9.50+/−0.02 kg.    -   13. Initiate mixing with mechanical stirrer.    -   14. Mix the solution for a minimum of 15 minutes or until the        solution is uniform, whichever is longer.    -   15. While mixing, adjust the pH of the solution to 7.30. Use the        1N HCl to adjust the pH down or the 1N NaOH to adjust the pH up.    -   16. Q.S. the solution to 10.16 kg with WFI.    -   17. Check the pH. If pH is outside 7.25-7.35 range use 1N HCl to        adjust the pH down, or 1N NaOH to adjust the pH up.    -   18. Sterile filter into an appropriate sterile receiving vessel.    -   19. Under aseptic conditions, fill the formulation into sterile        vials, stopper and cap vials.

Example 5. Combination Treatment with IT Riluzole and Oral Riluzole

To determine the tolerability and pharmacokinetics of a combination of adose of intrathecal (IT) and oral riluzole, four male mixed breed hounddogs were surgically implanted with an intrathecal catheter and wereadministered riluzole by a continuous 24 hour infusion over five days(Days 0 to 5) at a dose level of 0.2 mg/hour and also by one 50 mg oraltablet twice daily (every 12±4 hours) on Days 0 to 4 and once on Day 5which was approximately equal to a dose level of 1.8 to 2.1 mg/kg/dose.To prepare the intrathecal formulation, the appropriate amount ofvehicle (5% Trappsol® HPBCD-EC in 0.9% Sodium Chloride for Injection,USP) was mixed with the appropriate amount of riluzole powder at anominal concentration of 3.64 mg/mL. The intrathecal formulation wasprepared on the day prior to infusion and was filtered through a 0.22micron PVDF and stored at room temperature. The IT formulation wasadministered at a programmed infusion rate of 1.32 mL/day (i.e. 0.2mg/hour). The riluzole tablets were dispensed prior to dosing and werestored at room temperature.

Observations for morbidity, mortality, injury, and the availability offood and water were conducted twice daily for all animals. Clinicalobservations were conducted daily. Canine behavioral testing to assessmuscle tone, motor coordination, and state of arousal was conducteddaily beginning on Day 10. Neurological evaluations were conductedpretest, Day 1, and prior to necropsy. Body weights were measured andrecorded on Day −1 and 4. Physical examinations were conducted pretest,Day −1, and prior to necropsy. Blood, urine, and cerebrospinal fluid(CSF) samples were collected pretest, prior to necropsy, and atnecropsy. At study termination, necropsy examinations were performed,and designated tissues were collected and preserved for possible futuremicroscopic and bioanalytical analyses.

The results of this study demonstrated that continuous intrathecalinfusion of the test article at a dose of 0.20 mg/hr paired with twicedaily oral riluzole for five days was not associated with any mortality,clinical findings, body weight changes, motor or neurologic deficits, ormacroscopic observations. Intrathecal infusion of riluzole paired withoral administration of riluzole for 5 days resulted in goodbiodistribution throughout the spinal cord with highest levels ofriluzole in the tissue centered around the catheter tip and decreasinglevels more distal from the infusion site (FIG. 12B). Riluzole was alsofound throughout the brain.

A comparison of the data from this study to data from the dose rangefinding study described in Example 1 is provided in FIG. 12. The doserange finding study included a comparison between IT riluzole at 0.25mg/hour over a 5 day IT infusion period and oral riluzole equivalent to50 mg BID in humans. As shown in FIG. 12A, a combination dose of oraland IT riluzole did not substantially increase the amount of riluzolemeasured in the plasma as compared to an oral dose alone. FIG. 12B showsthat higher concentrations of riluzole are achieved in the spinal cordby IT administration as compared to oral administration, and combiningoral riluzole with IT riluzole appeared to have an additive effect.

Overall, the results of this study have established that a 5 daycontinuous intrathecal infusion of 0.2 mg/hr of riluzole paired withtwice daily oral administration of 50 mg of riluzole is well tolerated.In addition, the combination dose does not substantially increase theamount of riluzole measured in plasma samples, while providing greaterspinal cord concentrations than oral administration alone.

What is claimed is:
 1. A method for treating a subject in need thereof,the method comprising parenterally administering to the subject riluzoleat a dose that is less than 10 mg per day.
 2. The method of claim 1,wherein the parenterally administered daily dose is about 0.4 mg toabout 9.5 mg or about 0.4 mg to about 7.5 mg.
 3. The method of claim 1,wherein the parenterally administered daily dose is about 0.4 mg toabout 5 mg.
 4. The method of claim 1, wherein the parenterallyadministered daily dose is about 0.4 mg to about 4 mg.
 5. The method ofclaim 1, wherein the parenterally administered daily dose is about 0.1mg to about 4 mg.
 6. The method of claim 1, wherein the parenterallyadministered daily dose is about 1 mg to about 4 mg.
 7. The method ofclaim 1, wherein the parenterally administered riluzole is injected orinfused into the subject's brain, spinal cord, or a cerebral ventricle.8. The method of claim 1, wherein the parenterally administered riluzoleis intrathecally administered and, optionally, wherein administrationoccurs continuously.
 9. The method of claim 7, wherein parenteraladministration does not result in a substantial increase in serum AUC ofriluzole or a metabolite thereof.
 10. The method of claim 7, wherein thesubject is also orally administered riluzole.
 11. The method of claim 1,wherein the parenterally administered riluzole is formulated as acomposition comprising about 0.4 mg to about 10 mg per ml of riluzoledissolved in at least 1% (w/v) ß-cyclodextrin and an aqueous solvent,and wherein the composition a pH of about 5 to about
 8. 12. The methodof claim 11, wherein the parenterally administered riluzole compositioncomprises about 0.4 mg to about 10 mg per ml of riluzole dissolved inabout 1% (w/v) to about 15% (w/v) ß-cyclodextrin and an aqueous solvent.13. The method of claim 11, wherein the parenterally administeredparenterally administered riluzole composition comprises about 0.4 mg toabout 10 mg per ml of riluzole dissolved in about 1% (w/v) to about 10%(w/v) ß-cyclodextrin and an aqueous solvent.
 14. The method of claim 11,wherein the parenterally administered riluzole composition comprisesabout 0.4 mg to about 4 mg per ml of riluzole dissolved in about 1%(w/v) to about 5% (w/v) ß-cyclodextrin and an aqueous solvent.
 15. Themethod of any one of claim 11, wherein the parenterally administeredriluzole composition further comprises one or more pharmaceuticallyacceptable excipient and/or one or more additional active ingredient.16. The method of claim 11, wherein the ß-cyclodextrin is selected fromthe group consisting of 2,6-di-O-methyl-β-cyclodextrin,2-hydroxypropyl-β-cyclodextrin, and sulfobutylether β-cyclodextrin. 17.The method of claim 11, wherein the aqueous solvent is water, saline, ordextrose.
 18. The method of claim 1, wherein treatment alleviates one ormore symptoms in the subject, delays progression of a disease in thesubject, slows progression of a disease in the subject, or extendssurvival of the subject.
 19. The method of claim 1, wherein the subjectin need of treatment with riluzole is a subject with motor neurondisease, spinal muscular atrophy, spinal cord injury, Parkinson'sdisease, Multiple Sclerosis, Alzheimer's disease, depression, TouretteSyndrome, general anxiety disorders, schizophrenia, or bipolar disorder.20. The method of claim 19, wherein the subject in need of treatmentwith riluzole is a subject with amyotrophic lateral sclerosis.